Combined trauma and toxic inhalation in war and disaster medicine: alveolar–capillary barrier failure and respiratory countermeasures

Abstract

Severe trauma induces systemic inflammatory responses that predispose the lung to secondary injury. Acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality following severe trauma, particularly in military and disaster settings where inhalation exposure to toxic combustion products frequently accompanies physical injury. Combustion-derived particles, irritant gases, and complex aerosols generated by explosions or fires may amplify trauma-induced pulmonary inflammation and accelerate alveolar–capillary barrier failure. This review highlights the interactions between hemorrhagic trauma and toxic inhalation that contribute to respiratory failure in combined injury settings. Hemorrhagic shock and tissue injury trigger systemic inflammation, endothelial dysfunction, and increased vascular permeability, while inhaled toxicants directly damage the pulmonary epithelium and endothelium. Together, these processes promote alveolar–capillary barrier disruption and progression toward ARDS. These mechanisms are particularly relevant in battlefield and disaster critical care settings where delayed evacuation, inhalation exposure, and limited respiratory support may aggravate progression toward severe respiratory failure. Current management remains largely supportive, but emerging therapeutic approaches aimed at preserving alveolar–capillary barrier integrity may offer future opportunities for respiratory protection. A better understanding of the interactions between trauma and toxic inhalation may help guide the development of respiratory countermeasures for trauma-associated ARDS.

Introduction

Severe trauma remains one of the leading causes of mortality and long-term morbidity worldwide, particularly in military and austere operational environments where injuries occur under complex and hazardous conditions [1–4]. Among trauma-related complications, acute respiratory distress syndrome (ARDS) remains a major determinant of morbidity and mortality with reported incidences in combat casualties ranging from 3% to 33% [5, 6]. Beyond the initial mechanical insult, trauma rapidly triggers systemic inflammatory responses that promote endothelial activation, increased vascular permeability, and disruption of the alveolar–capillary barrier, a central event in trauma-associated ARDS [7, 8]. Despite substantial advances in understanding these mechanisms, effective therapeutic strategies remain limited, and no pharmacological therapy has yet demonstrated consistent efficacy in preventing or reversing trauma-associated ARDS. In complex operational environments, trauma is frequently associated with exposure to inhaled toxicants [9]. These insults may occur simultaneously or sequentially and interact dynamically to amplify pulmonary inflammation and alveolar–capillary barrier dysfunction.

Hemorrhagic shock, together with direct tissue injury, is a major driver of trauma-induced lung vulnerability, inducing tissue hypoperfusion, and systemic inflammatory activation [10]. These alterations promote the release of damage-associated molecular patterns (DAMPs), activate innate immune pathways, and trigger neutrophil recruitment within the pulmonary microvasculature [11, 12]. Systemic hypoperfusion and ischemia–reperfusion further promote endothelial activation, vascular permeability, pulmonary edema, and impaired gas exchange [13–15]. These mechanisms promote endothelial activation, increase vascular permeability, and disrupt the alveolar–capillary barrier. Trauma-associated ARDS likely represents a biologically heterogeneous syndrome involving distinct inflammatory, endothelial, and epithelial phenotypes [7, 16]. In addition, trauma-induced endotheliopathy characterized by glycocalyx degradation, endothelial dysfunction, dysregulated coagulation, and microvascular immunothrombotic responses may further amplify vascular leak and inflammatory injury, thereby contributing to progressive alveolar–capillary barrier failure [17].

In military and disaster settings, trauma frequently occurs in complex exposure environments involving multiple physical and chemical stressors rather than isolated insults. In addition to hemorrhagic shock, inhalation of toxic combustion products, including irritant gases and particulate matter generated by explosions, fires, or confined environments may further exacerbate pulmonary injury [9, 18, 19]. Recent conflicts and disaster scenarios have highlighted the respiratory risks associated with burn pits, fuel combustion, confined atmospheres, and structural fires, all of which generate chemically complex aerosols capable of aggravating trauma-associated lung injury [20–22]. These exposures may directly injure the pulmonary epithelium and endothelium, promote oxidative stress, and converge with trauma-induced systemic inflammation to accelerate barrier failure [5, 23–26]. This framework supports a combined or multi-hit injury paradigm in which trauma-induced systemic responses and inhaled toxicants dynamically interact to amplify pulmonary inflammation and accelerate alveolar–capillary barrier dysfunction (Fig. 1).

Fig. 1.

Conceptual model of combined trauma and toxic inhalation converging toward alveolar–capillary barrier dysfunction. Trauma-induced systemic responses, including hemorrhagic shock, tissue injury, and the release of damage-associated molecular patterns (DAMPs), promote systemic inflammation and immune activation. In parallel, inhalation of toxicants such as irritant gases and particulate matter induces pulmonary oxidative stress and epithelial–endothelial injury. These systemic and local insults may occur simultaneously or sequentially and interact dynamically rather than following a strictly sequential “two-hit” model. Their convergence promotes inflammatory and vascular amplification, disruption of epithelial–endothelial integrity, and increased permeability of the alveolar–capillary barrier. Collectively, these processes contribute to pulmonary edema, impaired gas exchange, and progression toward acute respiratory distress syndrome (ARDS). Created with Figure Labs

Experimental and clinical evidence increasingly suggests that combined injuries involving trauma and inhalation exposures may synergistically accelerate the progression toward severe lung dysfunction and ARDS [5, 19, 27]. However, the mechanisms linking trauma-induced systemic inflammation, inhaled toxicants, and alveolar–capillary barrier failure remain incompletely understood. This limits the development of early therapeutic strategies for trauma patients, particularly in prehospital and operational settings. Recent advances in targeted drug delivery and biomaterial-based approaches have opened new opportunities for respiratory countermeasures aimed at preserving alveolar–capillary barrier integrity following trauma and toxic inhalation [28, 29]. This review examines the emerging intersection between trauma-associated pulmonary injury and emerging therapeutic strategies. We first examine the mechanisms linking hemorrhagic trauma and inhalation of toxic agents to alveolar–capillary barrier dysfunction, with particular emphasis on endothelial injury, inflammatory amplification, and epithelial-endothelial interactions. We then discuss recent developments in targeted pulmonary therapeutic approaches that may enable innovative respiratory countermeasures in trauma medicine. Particular emphasis is placed on combined injury paradigms, operational critical care implications, and deployable interventions for military and austere care settings.

Trauma-induced lung vulnerability

Severe trauma, particularly when associated with hemorrhagic shock, induces a complex systemic response that can profoundly affect pulmonary physiology. Beyond the direct mechanical consequences of thoracic injury, trauma triggers a cascade of inflammatory and immune responses that predispose the lung to secondary injury [11, 12]. These responses are characterized by widespread activation of innate immune pathways, endothelial dysfunction, and dysregulation of coagulation, all of which contribute to pulmonary microvascular injury and increased permeability of the alveolar–capillary barrier [7, 16]. These alterations are increasingly recognized as part of a broader trauma-induced endotheliopathy contributing to vascular leak and organ dysfunction [17]. Hemorrhagic shock, together with direct tissue injury, plays a central role in this process. Severe blood loss results in systemic hypoperfusion and tissue ischemia, followed by reperfusion injury during resuscitation. This sequence promotes the release of damage-associated molecular patterns (DAMPs), including mitochondrial DNA, HMGB1, and extracellular ATP, which activate pattern recognition receptors and amplify systemic inflammation [30–32]. Systemic hypoperfusion and ischemia–reperfusion further promote endothelial activation, leukocyte recruitment, pulmonary microvascular dysfunction, and cytokine release within the lung [13, 33–35]. Neutrophils play a particularly important role in trauma-associated lung injury. Activated neutrophils adhere to the pulmonary endothelium and migrate into the interstitial and alveolar compartments, where they release proteases, reactive oxygen species, and neutrophil extracellular traps that contribute to epithelial and endothelial damage [34, 36]. Platelet–neutrophil interactions further amplify pulmonary inflammation and endothelial injury [12, 37]. Another critical feature of trauma-induced lung vulnerability is the disruption of the alveolar–capillary barrier. This barrier, formed by the close interaction between alveolar epithelial cells and pulmonary endothelial cells, is essential for maintaining gas exchange and fluid homeostasis in the lung. Trauma-associated inflammation disrupts epithelial and endothelial junctional integrity, increases vascular permeability, and promotes alveolar flooding, ultimately leading to impaired oxygenation and respiratory failure [8, 16]. Experimental studies have shown that systemic inflammatory mediators and oxidative stress can directly impair epithelial barrier function and increase paracellular permeability in the alveolar epithelium [8, 38]. Importantly, endothelial injury should not be considered merely secondary to epithelial damage, as pulmonary endothelial dysfunction itself represents a major driver of vascular leakage, inflammatory amplification, and edema formation during ARDS. The alveolar–capillary barrier therefore represents both a central site of injury and a potential therapeutic target. Mitochondrial dysfunction may further aggravate pulmonary injury by promoting oxidative stress, inflammatory signaling, and epithelial–endothelial damage [39–42]. Trauma-induced systemic responses create a state of heightened pulmonary susceptibility in which additional insults, including inhaled toxicants, may precipitate ARDS and support a multi-hit framework linking trauma and toxic exposures [7, 9, 11, 19, 35]. In military and disaster settings, where trauma victims may be exposed to smoke, chemical irritants, or particulate matter generated by explosions or fires, this trauma-induced vulnerability may significantly increase the risk of severe pulmonary complications. Understanding the mechanisms underlying this predisposition is therefore essential for the development of preventive strategies and targeted countermeasures aimed at preserving alveolar–capillary barrier integrity following trauma. This paradigm supports a combined or multi-hit framework in which trauma-induced systemic responses and inhalation exposures dynamically interact to amplify pulmonary inflammation, endothelial dysfunction, and alveolar–capillary barrier failure [9, 11, 19].

Toxic inhalation in combat environments

In modern combat and disaster environments, inhalation of toxic agents represents a major contributor to respiratory morbidity following trauma. Explosions, fires, industrial accidents, and destruction of infrastructure generate mixtures of irritant gases, particulate matter, and combustion-derived compounds that may directly damage the lung and amplify trauma-induced inflammatory responses [18, 19]. Combustion products are among the most common inhalation hazards encountered in military and disaster scenarios. Fires, explosions, and burning materials release toxic compounds including hydrogen chloride, nitrogen oxides, carbon monoxide, hydrogen cyanide, and particulate matter [5, 43]. Depending on their physicochemical properties, these agents may reach the distal lung and directly injure epithelial and endothelial cells [44]. Inhaled toxicants induce oxidative stress and inflammatory responses that disrupt epithelial and endothelial integrity and promote vascular leakage [7, 38, 43, 45, 46]. These processes contribute to mitochondrial dysfunction, barrier disruption, and amplification of pulmonary inflammation [39, 40, 47]. Particulate matter generated during explosions and combustion processes may also play a critical role in inhalation injury. Combustion-derived particles can deposit deep within the respiratory tract and promote oxidative stress, inflammatory responses, and epithelial barrier disruption. These particles may also contribute to systemic inflammatory and vascular effects following trauma [46–52]. Trauma victims exposed to inhaled toxicants frequently experience multiple physiological stressors simultaneously. Hemorrhagic shock, systemic inflammation, and inhalation injury may interact to amplify pulmonary inflammation, endothelial dysfunction, and alveolar–capillary barrier failure, supporting a multi-hit framework of combined lung injury [5, 19, 53]. These observations support a multi-hit framework in which trauma-induced systemic responses and inhalation injury interact to amplify pulmonary inflammation, endothelial dysfunction, and alveolar–capillary barrier failure.

Alveolar-capillary barrier failure

The integrity of the alveolar–capillary barrier is essential for maintaining pulmonary gas exchange and fluid homeostasis. This interface is formed by alveolar epithelial and pulmonary endothelial cells separated by a thin interstitial matrix [16, 38]. Disruption of this barrier represents a central event in the development of acute respiratory distress syndrome (ARDS) [7, 8]. Both epithelial and endothelial dysfunction contribute to pulmonary edema, impaired gas exchange, and respiratory failure during ARDS [54, 55]. The principal cellular and molecular mechanisms contributing to alveolar–capillary barrier disruption in this context are summarized in Table 1 and illustrated in Fig. 2. Trauma-induced systemic inflammation alters alveolar–capillary barrier integrity through endothelial activation, increased vascular permeability, and neutrophil recruitment [35]. Activated neutrophils release proteolytic enzymes, reactive oxygen species (ROS), and neutrophil extracellular traps, all of which contribute to epithelial and endothelial damage [36, 37]. Together, these mechanisms promote barrier dysfunction and pulmonary edema. Inhaled toxicants can directly damage epithelial and endothelial cells within the distal lung. Epithelial injury increases barrier permeability and impairs alveolar repair mechanisms, thereby aggravating pulmonary dysfunction [8, 26, 40, 56].

Table 1.

Key mechanisms contributing to alveolar–capillary barrier dysfunction and ARDS following hemorrhagic trauma and toxic inhalation

Pathophysiological process	Mechanisms involved	Representative mediators or pathways	Potential therapeutic targets	Key references
Systemic inflammatory priming after trauma	Hemorrhagic shock, ischemia–reperfusion injury, release of DAMPs	HMGB1, mitochondrial DNA, ATP, complement activation	Immune modulation, anti-inflammatory therapies	[11, 12]
Neutrophil-mediated injury	Recruitment and activation of neutrophils in pulmonary microvasculature	ROS production, proteases, neutrophil extracellular traps (NETs)	Anti-oxidants, neutrophil-targeted therapies	[34, 36]
Oxidative stress and mitochondrial dysfunction	Excessive ROS generation and mitochondrial damage	Mitochondrial ROS signaling, oxidative stress pathways	Mitochondria-targeted antioxidants	[39, 40, 62]
Epithelial barrier disruption	Tight junction breakdown and epithelial cell death	Claudins, occludin, epithelial apoptosis pathways	Barrier-protective therapies	[8, 38]
Endothelial dysfunction	Cytoskeletal contraction and vascular permeability	RhoA signaling, NF-κB activation	Endothelial stabilizing therapies	[84]
Inhaled toxicant injury	Irritant gases and combustion particles damaging lung tissue	NO₂, chlorine, carbon black nanoparticles	Anti-oxidants, anti-inflammatory therapies	[46, 50, 51]
Combined trauma–toxicant injury	Trauma-induced inflammatory priming amplifying toxicant effects	Systemic inflammation, oxidative stress amplification	Targeted respiratory countermeasures	[5, 19]

The table summarizes the principal pathophysiological processes involved in combined trauma and inhalation injury. Hemorrhagic shock promotes systemic inflammatory activation and endothelial dysfunction, whereas inhaled toxicants exacerbate oxidative stress, epithelial–endothelial injury, and vascular permeability. Together, these mechanisms contribute to alveolar–capillary barrier disruption, pulmonary edema, and progression toward ARDS. Abbreviations: DAMPs, damage-associated molecular patterns; NETs, neutrophil extracellular traps; ROS, reactive oxygen species

Fig. 2.

Mechanisms of alveolar–capillary barrier disruption following combined trauma and toxic inhalation. Hemorrhagic trauma induces systemic inflammatory responses characterized by the release of damage-associated molecular patterns (DAMPs), pro-inflammatory cytokines, and neutrophil recruitment within the pulmonary microvasculature. These responses promote oxidative stress and inflammatory injury affecting both epithelial and endothelial compartments. In parallel, inhaled toxicants such as irritant gases and particulate matter directly induce epithelial injury, oxidative stress, and mitochondrial dysfunction. The convergence of systemic and local insults disrupts epithelial–endothelial integrity, increases vascular permeability, and compromises alveolar–capillary barrier function. Mitochondrial dysfunction may further amplify oxidative stress and inflammatory signaling in both cellular compartments. Collectively, these mechanisms promote pulmonary edema, inflammatory cell infiltration, impaired gas exchange, and progression toward ARDS. Created with Figure Labs

Endothelial dysfunction also plays a critical role in barrier failure. Endothelial cells respond to inflammatory and oxidative stimuli by altering cell–cell junctions and increasing vascular permeability, resulting in microvascular leak [54, 57]. Hemorrhagic shock-associated hypoperfusion and ischemia–reperfusion responses further contribute to endothelial dysfunction through circulating inflammatory and oxidative mediators that promote endothelial permeability and microvascular leakage [58–60]. The resulting extravasation of protein-rich fluid into the alveolar space leads to pulmonary edema and impaired oxygenation, hallmarks of ARDS [7, 16]. Endothelial injury is therefore a major driver of vascular leakage and pulmonary edema during ARDS. Trauma-induced systemic responses may increase pulmonary susceptibility to inhalation injury and other secondary insults [5, 35]. These interactions may occur under simultaneous or sequential exposure conditions and amplify pulmonary injury [11, 19]. Exposure to inflammatory mediators or inhaled toxicants can impair mitochondrial function, resulting in oxidative stress, bioenergetic dysfunction, and epithelial–endothelial injury [39, 40, 61, 62]. Mitochondrial dysfunction may therefore represent a convergence pathway linking trauma-induced systemic stress with toxicant-induced cellular injury.

Collectively, these mechanisms highlight the central role of alveolar-capillary barrier disruption in the pathogenesis of lung injury following combined trauma and inhalation exposure. Strategies aimed at preserving alveolar–capillary barrier integrity may therefore help limit progression toward severe respiratory failure.

Functional biomaterials and deployable respiratory countermeasures

Despite advances in supportive care, no pharmacological therapy has consistently improved outcomes in trauma-associated ARDS, highlighting the need for innovative respiratory countermeasures. Functional biomaterials and targeted drug delivery systems offer promising strategies to locally modulate inflammation, oxidative stress, and epithelial–endothelial dysfunction while limiting systemic exposure (Fig. 3) [28]. Nanoparticle-based systems may enhance pulmonary delivery of anti-inflammatory, antioxidant, or RNA-based therapeutics while limiting systemic exposure [28, 63, 64]. Extracellular vesicles, including MSC-derived vesicles, have attracted considerable attention as endogenous nanocarriers capable of mediating intercellular communication and tissue repair [65, 66]. Experimental studies suggest that extracellular vesicles may reduce inflammation, preserve epithelial–endothelial integrity, and promote tissue repair, making them attractive multi-target therapeutic candidates for ARDS [67–69]. Beyond engineered biomaterials, several pharmacological agents with established safety profiles may represent valuable “off-the-shelf” therapeutic options for the management of trauma-induced lung injury. Drug repurposing strategies are particularly attractive in emergency or military settings where rapid deployment of treatments is required. Antioxidant molecules such as N-acetylcysteine have long been used to replenish intracellular glutathione stores and mitigate oxidative stress in pulmonary tissues [70]. Similarly, melatonin has been shown to exert potent anti-inflammatory and mitochondrial protective effects in experimental models of ARDS [71–73]. Mitochondria-targeted antioxidants, including compounds such as MitoQ or SkQ1, have also demonstrated potential in reducing oxidative stress and preserving mitochondrial function in inflammatory diseases (Fig. 3) [74]. By preserving mitochondrial function and reducing oxidative stress, these compounds may help limit epithelial–endothelial injury and alveolar–capillary barrier dysfunction. Other anti-inflammatory agents, including corticosteroids, have also been investigated, although their clinical benefits remain context dependent [7, 35]. Recent advances in biomaterial engineering have enabled the development of bioresponsive delivery systems that may improve therapeutic precision while limiting systemic exposure [28]. Combining targeted delivery technologies with repurposed pharmacological agents may facilitate the development of deployable respiratory countermeasures for trauma-associated ARDS. The main biomaterial-based therapeutic strategies investigated for trauma-associated ARDS are summarized in Table 2.

Fig. 3.

Biomaterial-based therapeutic strategies targeting lung injury following trauma and toxic inhalation. Emerging approaches based on functional biomaterials provide targeted strategies to mitigate alveolar–capillary barrier dysfunction. Nanoparticle-based systems enable localized delivery of anti-inflammatory and antioxidant agents to the injured lung. Extracellular vesicles (EVs) contribute to intercellular communication and promote tissue repair and immunomodulation. Mitochondria-targeted therapies aim to restore cellular bioenergetics and reduce excessive production of reactive oxygen species (ROS). In addition, stimuli-responsive biomaterials allow controlled drug release in response to local inflammatory or oxidative cues. Collectively, these strategies reduce inflammation and oxidative stress while promoting restoration of the alveolar–capillary barrier. Created with Figure Labs

Table 2.

Emerging biomaterial-based and targeted therapeutic approaches for trauma-associated ARDS

Therapeutic platform	Mechanism of action	Potential advantages for lung injury	Representative examples / references
Nanoparticle drug delivery systems	Targeted delivery of anti-inflammatory drugs, antioxidants or nucleic acids to injured lung tissue	Improved drug stability, localized pulmonary delivery, reduced systemic toxicity	[28, 63, 64]
Extracellular vesicles (EVs)	Transfer of proteins, lipids and regulatory RNAs that modulate inflammation and promote tissue repair	High biocompatibility, endogenous signaling properties, regenerative potential	[67, 68, 90, 91]
Mitochondria-targeted therapeutics	Reduction of mitochondrial oxidative stress and restoration of cellular bioenergetics	Protection of epithelial and endothelial cells against oxidative injury	[72, 74]
Bioresponsive biomaterials	Controlled release of therapeutic agents in response to oxidative stress or inflammatory signals	Stimulus-responsive drug delivery, improved therapeutic precision	[28]
Inhalable biomaterial formulations	Aerosolized delivery systems enabling direct drug deposition in the respiratory tract	Rapid onset of action, compatibility with emergency respiratory treatments	[63]

This table summarizes emerging biomaterial platforms and therapeutic strategies relevant to ARDS associated with hemorrhagic trauma and toxic inhalation. These approaches aim to modulate inflammation, oxidative stress, and mitochondrial dysfunction while preserving alveolar–capillary barrier integrity. Most remain experimental but illustrate potential strategies for limiting pulmonary injury and preventing progression toward severe respiratory failure

Experimental models and translational perspectives

Understanding the complex interactions between trauma, inhaled toxicants, and pulmonary barrier dysfunction requires experimental models capable of reproducing the structural and physiological complexity of the lung. Both in vitro and in vivo models have therefore been developed to investigate the mechanisms underlying ARDS and to evaluate potential therapeutic countermeasures [7, 16]. These complementary experimental systems provide mechanistic, physiological, and translational insights into trauma-associated pulmonary injury. Advanced in vitro models allow investigation of epithelial and endothelial responses to inflammatory and toxic stimuli [75–77]. Air–liquid interface models and multicellular co-culture systems have been developed, enabling more physiologically relevant investigation of epithelial–endothelial interactions during injury processes [78–80]. Recent advances in microengineering have also led to the development of lung-on-chip systems, which integrate microfluidic technology with cellular co-cultures to recreate dynamic aspects of lung physiology such as mechanical stretch, fluid flow, and immune cell trafficking [75, 81, 82]. Despite these advances, in vivo models remain essential for studying the systemic aspects of trauma-associated lung injury. Rodent models of hemorrhagic shock and resuscitation have been widely used to investigate the mechanisms of trauma-induced systemic inflammation and its effects on pulmonary function [11, 31]. Experimental exposure models involving toxic gases or combustion-derived particles have also improved understanding of inhalation injury and pulmonary barrier disruption [44, 83]. More recently, combined injury models integrating hemorrhagic shock with secondary pulmonary insults, including inhaled toxicants, infection, or mechanical ventilation, have been developed to better reproduce the complex mechanisms underlying trauma-associated ARDS [11, 35]. Additional models combining burn injury and smoke inhalation further emphasize the importance of clinically relevant combined injury paradigms capable of reproducing the dynamic progression of ARDS observed in operational settings [85]. Together, these complementary approaches provide valuable platforms for evaluating respiratory countermeasures for trauma-associated ARDS. Despite these advances, important limitations remain across current experimental models. In vitro systems incompletely reproduce systemic responses, whereas in vivo models are limited by species-specific differences and imperfect replication of operational exposure scenarios. Collectively, these limitations highlight persistent translational gaps and underscore the need for more standardized and clinically relevant modeling strategies. The main experimental models currently used to investigate trauma-associated ARDS and inhalation toxicology are summarized in Table 3.

Table 3.

Experimental models used to investigate trauma-associated ARDS and inhalation toxicology

Model type	Experimental system	Main applications	Advantages	Key references
In vitro epithelial models	Submerged airway or alveolar epithelial cell cultures	Cellular responses to toxicants, oxidative stress and inflammatory mediators	Controlled conditions, mechanistic studies	[79]
Air-liquid interface (ALI) models	Differentiated airway epithelial cultures exposed to airborne toxicants	Study of inhalation toxicology, epithelial barrier responses, and pollutant-induced signaling	Physiological exposure conditions reproducing airway differentiation and direct exposure to airborne agents	[78, 79, 93]
Co-culture barrier models	Epithelial-endothelial co-cultures reconstructing the alveolar-capillary barrier	Study of epithelial-endothelial interactions and barrier permeability	Improved representation of lung microenvironment	[80, 94, 95]
Lung-on-chip systems	Microfluidic devices integrating epithelial and endothelial cells under mechanical stretch	Investigation of complex lung physiology and drug responses	Dynamic physiological conditions	[81, 82]
Animal models of trauma	Hemorrhagic shock and resuscitation models in rodents	Study of systemic inflammatory responses and organ injury	Integrated physiological responses	[11, 31]
Inhalation injury models	Experimental exposure to toxic gases or particulate matter using controlled inhalation systems (e.g., nose-only or whole-body exposure)	Study of lung injury mechanisms and inflammatory responses following toxic inhalation	Controlled and reproducible exposure to inhaled toxicants in vivo	[44, 96]
Combined injury models	Experimental models combining hemorrhagic trauma with secondary pulmonary insults such as inhaled toxicants, infection, or mechanical ventilation	Investigation of “multi-hit” mechanisms of lung injury and interaction between systemic inflammatory priming and pulmonary toxic exposures	Improved representation of complex exposure scenarios encountered in trauma, disaster, or military environments	[11, 27, 35]
Military-relevant inhalation models	Whole-body inhalation of combustion-derived nanoparticles	Simulation of burn pit–related exposures	Translational relevance for operational environments	[83]

This table summarizes the principal in vitro and in vivo experimental systems used to study the pathophysiology of ARDS associated with hemorrhagic trauma and toxic inhalation. These models provide complementary approaches for investigating alveolar–capillary barrier dysfunction, inflammatory responses, and inhalation injury, while supporting the evaluation of emerging therapeutic strategies and respiratory countermeasures

Critical care and operational implications

Combined trauma and toxic inhalation injuries represent particularly challenging situations in critical care medicine due to the simultaneous occurrence of systemic inflammatory activation, respiratory dysfunction, endothelial injury, and impaired tissue oxygenation. In both military and civilian disaster settings, patients exposed to blast injury, hemorrhagic shock, structural fires, confined atmospheres, or combustion-derived toxicants may rapidly develop severe ARDS characterized by pulmonary edema, endothelial leak, and refractory hypoxemia [5, 7, 16]. These combined injuries frequently evolve within a broader context of multi-organ dysfunction involving circulatory instability, coagulation abnormalities, and systemic inflammatory responses, thereby increasing the complexity of respiratory management in critically ill patients [11, 12, 35].

The heterogeneous nature of trauma-associated ARDS represents a major challenge for intensive care management. Combined epithelial-endothelial injury induced by trauma and toxic inhalation may generate highly variable pulmonary permeability patterns, regional ventilation–perfusion mismatch, diffuse inflammatory infiltration, and altered pulmonary compliance [8, 54]. These alterations may contribute to severe oxygenation impairment requiring advanced respiratory support strategies.

Mechanical ventilation therefore remains a cornerstone of supportive care in trauma-associated ARDS, although respiratory support itself may contribute to secondary pulmonary injury. Ventilator-induced lung injury remains an important concern, particularly in severely injured lungs [35, 86]. Mechanical ventilation may therefore act as an additional contributor to lung injury within an already vulnerable pulmonary environment.

Protective ventilation strategies including low tidal volume ventilation, limitation of plateau pressure, and prone positioning have significantly improved outcomes in ARDS patients and remain central components of intensive care management [87, 88]. Nevertheless, implementation of these approaches may be particularly challenging in operational and disaster environments characterized by constrained resources, limited monitoring capabilities, and delayed evacuation. In battlefield medicine and prolonged field care settings, critically injured patients may experience prolonged exposure to hypoxemia, smoke inhalation, and inflammatory stress before transfer to specialized intensive care facilities [3, 4].

Such operational constraints may substantially increase the risk of progression toward severe respiratory failure and multi-organ dysfunction.

In addition to ventilation-related challenges, inhalation injuries occurring in military and disaster contexts frequently involve complex mixtures of toxic gases, combustion-derived particles, and thermal injury. Urban warfare, industrial explosions, tunnel fires, burn pits, and confined-space combustion generate chemically heterogeneous aerosols capable of inducing extensive epithelial and endothelial injury within the distal lung [18–20]. In mass casualty situations or austere environments, limited access to respiratory monitoring, oxygen delivery, and advanced ventilatory support may further complicate patient management. These considerations highlight the importance of integrating inhalation toxicology into broader frameworks of operational critical care and disaster medicine.

For the most severe forms of trauma-associated ARDS, extracorporeal membrane oxygenation (ECMO) may represent a rescue therapeutic option capable of temporarily supporting gas exchange while limiting ventilator-associated injury [89]. However, the implementation of ECMO remains technically demanding and resource intensive, requiring highly specialized personnel, advanced infrastructure, and complex logistical coordination that may not be readily available in operational or disaster settings. Its limited deployability in austere environments reinforces the importance of early interventions aimed at preserving alveolar–capillary barrier integrity.

Within this framework, rapidly deployable respiratory countermeasures may represent an important emerging objective in operational critical care. Biomaterial-based approaches, inhalable formulations, extracellular vesicle therapies, and mitochondria-targeted therapeutics may offer opportunities for localized modulation of oxidative stress, inflammatory amplification, and endothelial dysfunction during the early phases of lung injury [28, 29]. Inhalable nanoparticle formulations and aerosolized therapies may be particularly attractive in this context because they allow direct pulmonary targeting while potentially limiting systemic adverse effects and simplifying administration in prehospital environments [63, 64].

Future advances in battlefield and disaster critical care will likely require greater integration between trauma biology, inhalation toxicology, pulmonary critical care, and translational biomaterials research. Preservation of alveolar–capillary barrier integrity may therefore represent a key therapeutic objective for limiting progression toward severe ARDS and multi-organ failure. The operational and translational framework linking combined trauma, toxic inhalation, alveolar–capillary barrier dysfunction, ARDS progression, critical care constraints, and deployable respiratory countermeasures is summarized in Fig. 4.

Fig. 4.

Operational framework linking combined trauma, toxic inhalation, and ARDS in military and disaster medicine. Combined trauma and toxic inhalation injuries promote systemic inflammation and pulmonary injury that converge toward alveolar–capillary barrier dysfunction. In battlefield and disaster environments, hemorrhagic shock, blast injury, smoke inhalation, combustion-derived particles, and irritant gases contribute to pulmonary edema, impaired gas exchange, and progression toward acute respiratory distress syndrome (ARDS). Critical care management may require protective mechanical ventilation, oxygen therapy, and rescue interventions such as extracorporeal membrane oxygenation (ECMO), although operational constraints including delayed evacuation, austere care environments, and limited resources may complicate patient management. Emerging respiratory countermeasures aimed at preserving alveolar–capillary barrier integrity may help limit progression toward severe respiratory failure in operational critical care settings. DAMPs: damage-associated molecular patterns; ROS: reactive oxygen species; VILI: ventilator-induced lung injury. Created with Figure Labs

Conclusion and future directions

Combined trauma and toxic inhalation injuries represent a major challenge in both civilian and military medicine. Hemorrhagic shock and systemic inflammation can profoundly alter pulmonary homeostasis, creating a state of heightened vulnerability in which additional exposures, including toxic inhalation, may contribute to severe disruption of the alveolar-capillary barrier and progression toward acute respiratory distress syndrome. This paradigm is increasingly reflected in the emerging concept of trauma-toxicology, which emphasizes the dynamic interplay between systemic injury, inhaled toxicants, alveolar–capillary barrier dysfunction, and dysregulated inflammatory responses [9]. These insults may interact dynamically to amplify pulmonary injury and accelerate progression toward ARDS, supporting integrated multi-hit frameworks that better reflect operational and disaster-related exposure scenarios [92]. Improved understanding of these convergent injury pathways may facilitate identification of therapeutic targets and development of more effective interventions for trauma-associated ARDS. Recent advances in biomaterials science and targeted drug delivery technologies have opened promising perspectives for the development of novel respiratory countermeasures. Nanoparticle-based delivery systems, extracellular vesicles, and bioresponsive materials offer innovative approaches for modulating inflammation, oxidative stress, and mitochondrial dysfunction within the pulmonary microenvironment. Future research should integrate mechanistic insights with clinically relevant experimental models capable of reproducing combined trauma and inhalation injury. Improved characterization of trauma–toxicant interactions and identification of clinically relevant biomarkers will be important for advancing translational research and preserving pulmonary barrier integrity. Future battlefield and disaster critical care strategies will likely benefit from rapidly deployable respiratory countermeasures capable of preserving alveolar–capillary barrier integrity and limiting progression toward severe respiratory failure in operational and austere care environments.

Abbreviations

ARDS

Acute respiratory distress syndrome

ATP

Adenosine triphosphate

DAMPs

Damage-associated molecular patterns

DEP

Diesel exhaust particles

ECMO

Extracorporeal membrane oxygenation

EVs

Extracellular vesicles

HCl

Hydrogen chloride

HMGB1

High mobility group box 1

IL-1β

Interleukin-1 beta

IL-6

Interleukin-6

MSC

Mesenchymal stromal cells

MSC-EVs

Mesenchymal stromal cell-derived extracellular vesicles

NETs

Neutrophil extracellular traps

NF-κB

Nuclear factor kappa B

NOx

Nitrogen oxides

ROS

Reactive oxygen species

STAT3

Signal transducer and activator of transcription 3

TNF-α

Tumor necrosis factor alpha

VILI

Ventilator-induced lung injury

Author contributions

SD: Conceptualization, Writing – original draft, Visualization, Writing – review & editing.SS, SC, NP: Writing – review & editing.MV, MC: Supervision, Writing – review & editing.SF: Conceptualization, Supervision, Writing – review & editing.

Funding

This work did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Declaration of generative AI

During the preparation of this work, the authors used ChatGPT (OpenAI) to improve language clarity and readability and Figure Labs for conceptual figure drafting. The authors reviewed and edited all content and figures as needed and take full responsibility for the final content of the manuscript.